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EC number: 500-334-1 | CAS number: 154565-28-3
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Endpoint summary
Administrative data
Key value for chemical safety assessment
Effects on fertility
Description of key information
An OECD 422 screening study is available for the submission substance and reports a NOAEL of 1000 mg/kg bw/d.
Link to relevant study records
- Endpoint:
- screening for reproductive / developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 10 November 2017 - 6 January 2018 (in-life)
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Reason / purpose for cross-reference:
- reference to same study
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
- Version / remarks:
- July 29, 2016
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
- Specific details on test material used for the study:
- Epoxypropyl neodecanoate, oligomeric reaction products with cyclohexane-1,2-dicarboxylic anhydride
and propylidenetrimethanol (HP1365)
Stability: 12 days ambient and refrigerated (2 to 8¿C), as established in MPI Research Study 2622-00
1
Correction Factor: 1.029 (purity 97.2%)
Storage Conditions: Room temperature
Date Received: June 21, 2017
Received From: PPG Industries Italia S.r.l. Quattordio, Italy
Label Identification: Epoxypropyl Neodecanoate, Oligomeric Reaction Products with Cyclohexane-1,2
Dicarboxylic Anhydride and Propylidenetrimethanol
Lot Number: CVR 83297
Physical Characteristics: Clear, yellow gel
Expiration Date: December 27, 2018
Storage: Controlled room temperature, protected from light
TMC Number: 1705BB - Species:
- rat
- Strain:
- Sprague-Dawley
- Details on species / strain selection:
- Rat: CD®[Crl:CD®(SD)]. The rat is the usual rodent model used for evaluating the toxicity of various classes of chemicals and for which there is a large historical database.
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Laboratories
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: 8 weeks
- Weight at study initiation: 267-307 g (M), 174-220 g (F)
- Fasting period before study: No
- Housing: Individually, except during pairing, near parturition, and during lactation.
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 2 weeks
DETAILS OF FOOD AND WATER QUALITY:
Block Lab Diet (Certified Rodent Diet #5002, PMI Nutrition International, Inc.) was available ad libitum, except during designated periods (overnight prior to clinical pathology blood sample collection intervals). The lot number from each diet lot used for this study was recorded. Certification analysis of each diet lot was performed by the manufacturer. Tap water was available ad libitum via an automatic watering system. The water supply is monitored for specified contaminants at periodic intervals according to SOP. The results of food and water analyses are retained in the Archives. The Study Director was not aware of any potential contaminants likely to be present in the diet or water that would have interfered with the results of the study. Therefore, no analyses other than those stated above were conducted.
ENVIRONMENTAL CONDITIONS
- Temperature (°C):
20-26
- Humidity (%): 30-70
- Photoperiod (hrs dark / hrs light):
12/12
IN-LIFE DATES: From: 10 November 2017 To: 6 January 2018 - Route of administration:
- oral: gavage
- Details on exposure:
- Animals were dosed daily by gavage at dose levels of 0, 100, 300, and 1000 mg/kg bw/d and a dose volume of 10 mL/kg bw. The vehicle and test article formulations were continually stirred prior to and throughout dose administration. Individual doses were based on the most recent body weights.
- Details on mating procedure:
- On Day 15, each Repro/Dev Tox female was housed in the cage of a male from the same treatment group. Positive evidence of copulation was established by daily inspection for a copulatory plug in the vagina and/or the presence of sperm in the vaginal lavage. The day on which positive evidence of copulation was observed was considered GD 0. After evidence of mating was observed, the female was returned to an individual cage for the remainder of the study. The maximum pairing period was 14 days, at the end of which any females with no confirmed evidence of mating were returned to individual cages until scheduled euthanasia. 28-Day Tox females and animals designated for the recovery period were not cohabitated.
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Samples were taken from dosing preparations for the assessment of achieved concentration and homogeneity. Samples were collected while the preparations are being stirred. All analytical work was conducted by MPI Research, Mattawan, MI using an analytical method developed by MPI Research and validated under MPI Research Study Number 2622-001.
- Duration of treatment / exposure:
- The males were dosed for 2 weeks prior to mating and through the mating period for a total of 28 days. Females used for reproductive/developmental toxicity assessment were dosed for 2 week prior to mating and through the mating period. Females that delivered and retained litters were dosed to LD13. Females that did not deliver and did not have evidence of mating were dosed for 24 days after the cohabitation period ended. Females used for toxicity assessment were dosed for 28 days. The recovery males and recovery females, which were not cohabitated, were dosed for 28 days and then remained on study for a 14-day recovery period.
- Frequency of treatment:
- Daily
- Details on study schedule:
- Daily, with the exception of recovery animals
- Dose / conc.:
- 0 mg/kg bw/day (actual dose received)
- Remarks:
- Vehicle (PEG 400) control
- Dose / conc.:
- 100 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 300 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 1 000 mg/kg bw/day (nominal)
- No. of animals per sex per dose:
- 10/sex (reproductive/developmental toxicity assessment)
10/sex (toxicity assessment)
5/sex (recovery groups) - Control animals:
- yes, concurrent vehicle
- Details on study design:
- The dose levels were selected on the basis of available data from a 14-day oral toxicity study in rats (MPI Research Study Number 2622-0037). No adverse findings were observed on body weights, food consumption, and macroscopic findings at dose levels ¿1000 mg/kg bw/d in the 14-day study. The only clinical observation was piloerection in a few animals in each dose group (100, 300, and 1000 mg/kg bw/d) on the last day of testing. The high dose level for this study was selected in accordance with the maximum dose level recommended in the testing guidance and the lower doses for determination of a dose-response. 10 rats/sex/group were assigned to the reproductive/developmental toxicity assessment. Males were treated for 14 days prior to mating and during mating, for at least 28 days. Females were treated for 14 days prior to mating, during mating, gestation and lactation (to LD13). 10 rats/sex/group were assigned to the toxicity assessment and were treated for 28 days. An additional 5 rats/sex (control and high dose groups) were treated for 28 days followed by a 14-day recovery period.
- Positive control:
- Not required for this study type.
- Parental animals: Observations and examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: at least twice daily. All animals were observed for morbidity, mortality, injury, and the availability of food and water. General clinical observations (health condition including behavioural changes and signs of toxicity) were made daily post-dosing.
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Pre-test and weekly during the study, post-dosing. Observations included, but were not limited to, evaluation of the skin, fur, eyes, ears, nose, oral cavity, thorax, abdomen, external genitalia, limbs and feet, as well as evaluation of respiration.
BODY WEIGHT: Yes
- Time schedule for examinations: Males (weekly and on FOB and locomotor activity days). Repro/Dev Tox females: Weekly (during oestrous evaluations and prior to mating), GD 0, 7, 14, and 20; PND 0 and 4, 7, and 13. Body weight change was calculated for the males and females between each weighing interval and over the entire premating and recovery period and for the Repro/Dev Tox females on GD 0-7, 7-14, 14-20, 0-20 and PND 0-4, 4-7, 7-13 and 0-13.
FOOD CONSUMPTION: Yes
Males and 28-Day Tox Females: Weekly
Repro/Dev Tox Females: Weekly (during oestrous evaluations and prior to mating), GD 0, 7, 14, and 20; PND 0, 4, 7, and 13.
Recovery animals: Weekly
Food consumption was not recorded during mating as animals were cohoused.
WATER CONSUMPTION: No
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: Yes (overnight fasted)
All males, 28-Day Tox females and recovery animals (Day 29 and prior to recovery necropsy). Prothrombin time, Activated partial thromboplastin time, fibrinogen; leukocyte count (total and absolute differential), erythrocyte count, haemoglobin, haematocrit, mean corpuscular hemoglobin, mean corpuscular volume, mean corpuscular hemoglobin concentration (calculated), absolute reticulocytes, platelet count, RDW. Blood smears were preserved and stained for possible future evaluation.
CLINICAL CHEMISTRY: Yes (overnight fasted)
All males, 28-Day Tox females and recovery animals (Day 29 and prior to recovery necropsy). Alkaline phosphatase, total bilirubin (with direct bilirubin if total bilirubin exceeds 1 mg/dL), aspartate aminotransferase, alanine aminotransferase, urea nitrogen, creatinine, total protein, albumin, globulin and A/G (albumin/globulin) ratio (calculated), glucose, total cholesterol, triglycerides, electrolytes (sodium, potassium, chloride), calcium, phosphorus, bile acids. Additionally, blood was collected from all Repro/Dev Tox females delivering a litter and all males at necropsy for TSH and T4 hormone analysis.
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: No
IMMUNOLOGY: No - Oestrous cyclicity (parental animals):
- All P females pre-exposure for 2 weeks (selection of only normal cycling females to continue on study), during the 2-week pre-mating dosing period, 14-day cohabitation period until evidence of copulation was detected, and at terminal necropsy.
- Sperm parameters (parental animals):
- Not investigated
- Litter observations:
- Toward the end of the gestation period, females were examined twice daily for signs of parturition. The mated females were allowed to give birth (F1). Any female dying during parturition was subjected to gross necropsy, The duration of gestation was calculated, and any difficulties occurring at parturition recorded. The day on which all pups were delivered was designated LD0. The litters were examined as soon as possible after delivery. The following parameters were recorded for each litter. Litter size (total number live born pups, stillborn pups and partially cannibalized pups); Number of stillborn pups; Number of live born pups; Number of pups per sex; Individual pup body weights; Gross abnormalities of the pups. Litters were culled on LD4 to 8 pups (4/sex where possible). Blood was collected for TSH and T4 from at least two pups per litter (pooled) on LD4.
Litters weere housed with their dams to LD13. The dams and litters were observed daily for survival and behavioural alterations in nesting and nursing, and the presence of dead pups recorded. Pups were individually weighed and examined externally on LD0, 4, 7, and 13. The dam and litter remained together until LD 13. Anogenital distance was recorded for all pups on LD4 (post-cull) and the number of nipples counted on male pups on PND 12. - Postmortem examinations (parental animals):
- Gross necropsy was performed all surviving males and all 28-day Tox females. For the Repro/Dev Tox females, gross necropsy was performed and the number of implantation scars recorded. The uteri from non-gravid females were stained with ammonium sulphide for the detection of implantation sites. Weights of the adrenals, brain, epididymides, heart, kidneys, liver, lungs, ovaries, prostate, seminal vesicles, spleen, testes, thymus, thyroid and uterus were recorded.
- Postmortem examinations (offspring):
- F1 pups will be euthanised on LD 4 were externally examined. Blood samples (pooled from at least 2 pups per litter) for T4 and TSH were collected. Any abnormalities were recorded and the carcasses discarded. The thyroid was collected from 1 F1 pup/sex sacrificed on LD 13. All F1 pups were externally examined. Any abnormalities were recorded, and the carcasses will be discarded. If a skeletal anomaly was suspected, the pups were eviscerated, cleared, and stained with Alizarin Red S and examined using Dawson's technique. The thyroid gland was collected from
one pup/sex/litter and saved in 10% neutral buffered formalin for possible histopathological evaluation. - Statistics:
- Raw data were tabulated within each time interval, and the mean and standard deviation and/or incidence counts (categorical variables) calculated for each endpoint by sex and group. For each endpoint, treatment groups were compared to the control group. Data for some endpoints, as indicated, were transformed by either a log or rank transformation prior to conducting the specified analysis. All analyses were two-tailed for significance levels of 5% and 1%. All means were presented with standard deviations. All statistical tests were performed by a computer.
Group Pair-wise Comparison (General ANOVA)
Endpoints: Parental In-life Data, Body Weights and Body Weight Change-Males, Premating and Gestation Body Weight and Body Weight Change-Females, Premating Food Consumption-Males and Females, Gestation Food Consumption, Postmating Food Consumption-Males, Haematology (except leukocyte counts), Coagulation, Clinical Chemistry, FOB, Lactation Body Weights (P), Lactation Body Weight Change (P), Lactation Food Consumption (P), Fertility Indices, Copulatory Interval, Gestation Length (P), Litter Size, Viable Pups, Stillborn Pups, Pathology, Organ Weights (Absolute Weights, Relative to Body and Brain Weights).
Generalized Linear Model:
Locomotor Activity (Continuous), Basic Movements, Fine Movements, Rearing, Distance.
Fisher¿s Exact Test with Stepdown Sidak Adjustment:
Male Fertility Index, Female Fertility Index, Female Mating Index, Male Mating Index, Female Fecundity Index, Male Fecundity Index, Gestation Index.
Arcsin-Square Root Transformation:
Pup Sex Ratio (% viable males/litter), Stillborn Index, Pup Survival (Days 0-4 pre-cull and 4-post-cull-Day 13)
Exact Mantel-Haenszel Test with Stepdown Sidak Adjustment:
Categorical FOB data
Covariate Analysis:
Pup Weights - Reproductive indices:
- Male Fertility Index
Female Fertility Index
Female Mating Index
Male Mating Index
Female Fecundity Index
Male Fecundity Index
Gestation Index - Offspring viability indices:
- Viability Index
Survival Index - Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- No adverse test article-related effects were noted on general clinical observations in females at any of the dose levels evaluated. There were observations of salivation in the 100, 300, 1000 mg/kg bw/d dose groups (1 of 10, 1 of 9, and 1 of 7 females, respectively) during the mating and gestation periods. Other observations noted during the course of the study were not considered treatmnet-related due to a low incidence, concurrent finding in control animals, and/or expected findings for rats of this strain.
No adverse test article-related effects were noted on detailed clinical observations in females at any of the dose levels evaluated. In the females, there were observations of salivation in the 100 and 1000 mg/kg bw/d dose groups (1 of 10 and 3 of 10 females, respectively) during the premating period and in the 300 mg/kg/bw/d group (1 of 9 females) during the lactation period. While the increased observation of salivation may be treatment-related, there was no impact on the overall health of the animals, and therefore not considered adverse. Other observations noted during the course of the study were not considered treatment-related due to a low incidence, concurrent finding in control animals, and/or expected findings for rats of this strain. - Dermal irritation (if dermal study):
- not examined
- Mortality:
- mortality observed, non-treatment-related
- Description (incidence):
- One control female was found dead on Study Day 36. There were no clinical observations, body weight loss, or decrease in caged food consumption for this animal prior to being found dead. All other animals in the Repro/Dev Tox phase survived to the scheduled study termination.
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- No treatment-related effects were observed on mean body weight or body weight change in the females at any of the dose levels evaluated. The few statistically significant differences observed in these data between the control and treated groups occurred sporadically and often due to the directions of the change were considered incidental and unrelated to treatment.
- Food consumption and compound intake (if feeding study):
- no effects observed
- Description (incidence and severity):
- No treatment-related effects were observed on caged food consumption in the females at any of the dose levels evaluated. The few statistically significany increases observed in these data between the control and treated groups occurred sporadically, lacked dose-responsiveness, and were considered incidental and unrelated to treatment.
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Description (incidence and severity):
- FOB and motor assessment were assessed in this study in animals assigned to the toxicity group and are reported separately.
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Histopathological findings: non-neoplastic:
- not examined
- Histopathological findings: neoplastic:
- not examined
- Other effects:
- no effects observed
- Reproductive function: oestrous cycle:
- effects observed, treatment-related
- Description (incidence and severity):
- No treatment-related effects were observed on mean cycle length in the Repro/Dev Tox females at any of the dose levels evacuated. At 300 and 1000 mg/kg bw/d there was a significant decrease in number of cycles compared to controls (-25 and -29%, respectively). While this decrease may be treatment-related, without effects on the reproductive and fertility parameters it was not considered adverse.
- Reproductive function: sperm measures:
- not examined
- Reproductive performance:
- no effects observed
- Description (incidence and severity):
- No effect of treatment was observed on mating, fertility or fecundity indices in males or females. These indices in each of the treated groups were comparable to control values. Likewise, the mean Copulatory Interval (mean days-to-mating) in the test article-treated groups which ranged from 2.6 to 3.9 days was comparable to the mean of 2.9 days in the control group.No test article-related effect was observed on parturition data in the P females at any of the dose levels evaluated. Pregnancy rates for the P females were 80, 100, 90, and 80%, providing 7, 10, 9, and 8 litters with viable pups in the control, 100, 300, and 1000 mg/kg bw/d groups, respectively. Parturition parameters (i.e., incidence of animals with stillborn pups, mean number of pups at birth [liveborn, stillborn and total], Gestation Index, Stillborn Index, and mean number of uterine implantation scars at necropsy) in the treated groups were comparable to controls.
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Remarks on result:
- not determinable due to absence of adverse toxic effects
- Key result
- Critical effects observed:
- no
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- No effect of treatment was observed from F1 pup detailed clinical observations at any of the dose levels evaluated. The few findings observed in the pups from the treated groups occurred at low incidence or with similar frequency to controls and were considered unrelated to treatment.
- Dermal irritation (if dermal study):
- not examined
- Mortality / viability:
- no mortality observed
- Description (incidence and severity):
- No effect of treatment on F1 pup survival over LD 0-4 or LD 4-13 was observed in the treated groups in comparison to controls. Mean pup survival LD 0-4 ranged from 95.37% to 99.31% in the treated groups and was comparable to controls at 97.62%. Mean pup survival was 100% in all groups over LD 4-13. Litter size in the treated groups on LD 4 pre- and post-cull, and at LD 13 was comparable to controls.
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- No treatment-related effect was observed on F1 pup body weights (male, female, and male and female combined) at any of the dose levels evaluated.
- Food consumption and compound intake (if feeding study):
- not examined
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Moderate increases in serum Thyroid Stimulating Hormone (TSH) concentrations on Lactation Day 4 were seen in pups from dams at 300 and 1000 mg/kg bw/d. There were no associated alterations in serum thyroxine (T4) concentrations or microscopic findings in the thyroid gland, and increases in TSH concentrations were not considered to be adverse.
- Urinalysis findings:
- not examined
- Sexual maturation:
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- No effects were observed from macroscopi examination of stillborn pups, pups dying on study, LD 4 culled pups, or LD 13 pups.
- Histopathological findings:
- not examined
- Other effects:
- no effects observed
- Description (incidence and severity):
- No treatment-related effect was observed on F1 pup anogenital distance or nipple count at any of the dose levels evaluated.
- Behaviour (functional findings):
- not examined
- Developmental immunotoxicity:
- not examined
- Key result
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Effect level:
- 1 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Remarks on result:
- not determinable due to absence of adverse toxic effects
- Key result
- Critical effects observed:
- no
- Key result
- Reproductive effects observed:
- no
- Conclusions:
- In the absence of any findings of toxicological significance, a parental NOAEL of 1000 mg/kg bw/d can be determined for this study. A reproductive NOAEL of 1000 mg/kg bw/d can also be determined in the absence of any effects on fertility or development.
- Executive summary:
This OECD 422 screening study was conducted to evaluate for possible adverse effects of the submission substance (epoxypropyl neodecanoate, oligomeric reaction products with cyclohexane-1,2-dicarboxylic anhydride and propylidenetrimethanol) following repeated dosing to male and female rats, including systemic toxicity, neurotoxic potential, reproductive performance (gonadal function, mating behavior, conception, development of the conceptus, and parturition), and F1 offspring growth and maturation up through LD 13. No effects on treated males and females were observed on survival, clinical observations, body weights and body weight change, food consumption, oestrous cycle parameters, reproductive performance (mating, fertility, and fecundity), behavioural evaluations (functional observational battery and locomotor activity), clinical pathology parameters, organ weights, macroscopic observations, and microscopic observations. No effects of treatment were observed on F1 survival, clinical observations, body weights, and macroscopic findings. Based on these findings, 1000 mg/kg bw/d, the highest dose level evaluated, was considered to be the NOAEL.
Reference
Summary of fertility parameters
|
0 |
100 |
300 |
1000 |
Males paired (#) |
9 |
10 |
10 |
10 |
Males mated (#) |
8 |
10 |
9 |
8 |
Males impregnating females (#) |
8 |
10 |
9 |
8 |
Male mating index |
88.9 |
100 |
90.0 |
80.0 |
Male fertility index |
88.9 |
100 |
90.0 |
80.0 |
Male fecundity index |
100 |
100 |
100 |
100 |
Females paired (#) |
10 |
10 |
10 |
10 |
Females mated (#) |
8 |
10 |
9 |
8 |
Females pregnant (#) |
8 |
10 |
9 |
8 |
Female mating index |
80.0 |
100 |
90.0 |
80.0 |
Female fertility index |
80.0 |
100 |
90.0 |
80.0 |
Female fecundity index |
100 |
100 |
100 |
100 |
Summary of findings in dams
|
F |
|||
|
0 |
100 |
300 |
1000 |
Mortality |
1 |
- |
- |
- |
Salivation |
- |
1 |
1 |
3 |
Bodyweight (g) pre-mating |
241.4 |
234.0 |
239.7 |
234.2 |
Bodyweight (g) GD20 |
414.0 |
401.9 |
395.0 |
383.6 |
Bodyweight (g) LD20 |
351.0 |
338.3 |
336.7 |
339.5 |
Weight gain (g) pre-mating |
41.2 |
37.2 |
42.0 |
35.5 |
Weight gain (g) gestation |
154.9 |
158.7 |
148.1 |
148.6 |
Weight gain (g) lactation |
30.9 |
32.8 |
31.3 |
41.1 |
Oestrus cycle length (d) |
4.6 |
4.7 |
4.6 |
5.6 |
[No. cycles] |
2.8 |
2.4 |
2.1* |
2.0* |
*significantly different to controls (p<0.05)
Summary of litter parameters
|
0 |
100 |
300 |
1000 |
Females on study (#) |
10 |
10 |
10 |
10 |
Females pregnant (#) |
8 |
10 |
9 |
8 |
Litters (#) |
7 |
10 |
9 |
8 |
Gestation length (d) |
21.4 |
21.6 |
21.5 |
21.8 |
Litter size (#) |
15.71 |
14.40 |
14.56 |
13.50 |
Stillborn (#) |
0.0 |
0.1 |
0.0 |
0.1 |
Summary of offspring viability and growth
|
0 |
100 |
300 |
1000 |
Live pups PND0 (#) |
15.7 |
14.3 |
14.6 |
13.4 |
Live pups PND4 (#) pre-cull |
15.3 |
13.6 |
14.4 |
13.1 |
Live pups PND4 (#) post-cull |
8.0 |
8.0 |
8.0 |
8.0 |
Live pups PND7 (#) |
8.0 |
8.0 |
8.0 |
8.0 |
Live pups PND13 (#) |
8.0 |
8.0 |
8.0 |
8.0 |
Viability index (%) |
97.6 |
95.4 |
99.3 |
98.0 |
PND 4-13 Survival index (%) |
100 |
100 |
100 |
100 |
Pup weight (g) PND0 |
6.51 |
6.45 |
6.36 |
6.63 |
Pup weight (g) PND4 |
9.92 |
9.79 |
10.08 |
10.00 |
Pup weight (g) PND7 |
15.94 |
16.24 |
16.17 |
16.35 |
Pup weight (g) PND13 |
31.07 |
30.17 |
31.20 |
31.41 |
AGD (mm) PND4 |
3.286 |
3.475 |
3.278 |
4.094 |
Summary of thyroid hormone measurements
|
0 |
100 |
300 |
1000 |
|
T4 (µg/dL) |
Pups PND4 |
2.701 |
2.715 |
3.003 |
3.116 |
Dams LD13 |
3.871 |
4.237 |
4.042 |
4.073 |
|
Pups LD13 |
7.674 |
7.898 |
8.331 |
8.095 |
|
Males Day 29 |
4.597 |
5.181 |
5.328 |
5.533 |
|
TSH (ng/dL) |
Pups PND4 |
1.687 |
2.603 |
4.329 |
8.664 |
Dams LD13 |
6.774 |
8.300 |
5.739 |
7.793 |
|
Pups LD13 |
4.921 |
5.554 |
5.501 |
3.890 |
|
Males Day 29 |
2.896 |
3.292 |
3.354 |
4.302 |
Effect on fertility: via oral route
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 1 000 mg/kg bw/day
- Study duration:
- subacute
- Species:
- rat
- Quality of whole database:
- A modern, guideline- and GLP-compliant OECD 422 screening study is avaialble for the submission substance.
Effect on fertility: via inhalation route
- Endpoint conclusion:
- no study available
Effect on fertility: via dermal route
- Endpoint conclusion:
- no study available
Additional information
No adverse effects of treatment were seen on parental toxicity, fertility or development in an OECD 422 study perfomred with the submission substance at dose levels of up to 1000 mg/kg bw/d. Post-dosing salivation observed in a small number of dams from all treated groups is likely to be treatment-related but is not considered to represent an adverse effect. Bodyweights and food consumption were unaffected by treatment. At 300 and 1000 mg/kg bw/d there was a significant decrease in number of cycles compared to controls (-25 and -29%, respectively); findings at the highest dose level are attributable at least in part to one dam with an oestrus cycle length of 11 days. While this decrease may be treatment-related, without effects on the reproductive and fertility parameters it was not considered adverse. No effects of treatment were seen on measures of fertility. Pup viability and growth were unaffected by treatment at any dose level. Moderate increases in serum Thyroid Stimulating Hormone (TSH) concentrations on Lactation Day 4 were seen in pups from dams at 300 and 1000 mg/kg bw/d. There were no associated alterations in serum thyroxine (T4) concentrations or microscopic findings in the thyroid gland, and increases in TSH concentrations were not considered to be adverse.
Effects on developmental toxicity
Description of key information
An OECD 422 screening study is available for the submission substance and reports a NOAEL of 1000 mg/kg bw/d; there are no additional data on developmental toxicity.
Effect on developmental toxicity: via oral route
- Endpoint conclusion:
- no adverse effect observed
- Dose descriptor:
- NOAEL
- 1 000 mg/kg bw/day
- Study duration:
- subacute
- Species:
- rat
- Quality of whole database:
- A modern, guideline- and GLP-compliant OECD 422 screening study is avaialble for the submission substance.
Effect on developmental toxicity: via inhalation route
- Endpoint conclusion:
- no study available
Effect on developmental toxicity: via dermal route
- Endpoint conclusion:
- no study available
Additional information
An OECD 422 screening study is available for the submission substance and reports a NOAEL of 1000 mg/kg bw/d; there are no additional data on developmental toxicity.
Justification for classification or non-classification
A screening study with the submission substance reports a NOAEL of 1000 mg/kg bw/d; no additional data are available. In the absence of any indication of reproductive or developmental toxicity, no classification for reproductive toxicity is proposed under CLP.
Additional information
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